Early work on excitotoxicity suggested that stroke and neurotrauma might be treated using drugs that block glutamate receptors (Albers, Archives in Neurology 49:418-420 (1992); Albers Ann Neurol 25:398-403 (1989)). Although early tests in vitro and in animal models were promising, unfortunately, all clinical stroke trials of glutamate antagonists to date have shown no benefit, and even toxic side effects (Davis et al., Lancet 349:32 (1997); Morris et al., J Neurosurg 91:737-743 (1999); Davis et al., Stroke 31:347-354 (2000); Ikonomidou et al., Proc Natl Acad Sci USA 97:12885-12890 (2000); Lees et al., Lancet 355:1949-1954 (2000)). A likely explanation is that the negative consequences of administering agents that inhibit excitatory neurotransmission in the CNS had outweighed their utility as neuroprotectants (Ikonomidou and Turski, Lancet Neurology 383-386 (2002). Glutamatergic signalling is required for CNS function and therefore, blocking essential excitatory neurotransmission has negative consequences (Ikonomidou, Biochem. Pharmacol. 62:401-405 (2001)). Thus, a more sophisticated approach to treating neuronal death is required to bypass the negative consequences of blocking glutamate receptors.
One of the present inventors has reported that postsynaptic density-95 protein (PSD-95) couples NMDARs to pathways mediating excitotoxicity and ischemic brain damage (Aarts et al., Science 298, 846-850 (2002)). This coupling was disrupted by transducing neurons with peptides that bind to modular domains on either side of the PSD-95/NMDAR interaction complex. This treatment attenuated downstream NMDAR signaling without blocking NMDAR activity, protected cultured cortical neurons from excitotoxic insults and reduced cerebral infarction volume in rats subjected to transient focal cerebral ischemia.